3ITN

Crystal structure of Pseudo-activated Procaspase-3

Summary for 3ITN

• Entry DOI: 10.2210/pdb3itn/pdb
• Related PRD ID: PRD_000238
• Descriptor: Caspase-3, ACETYL-ASP-GLU-VAL-ASP-CHLOROMETHYL KETONE inhibitor (3 entities in total)
• Functional Keywords: caspase-3, apoptosis, hydrolase, phosphoprotein, protease, s-nitrosylation, thiol protease, zymogen, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: P42574
• Total number of polymer chains: 2
• Total formula weight: 29168.53

Authors

Walters, J.,Pop, C.,Scott, F.L.,Drag, M.,Swartz, P.D.,Mattos, C.,Salvesen, G.S.,Clark, A.C. (deposition date: 2009-08-28, release date: 2010-03-02, Last modification date: 2023-09-06)

Primary citation

Walters, J.,Pop, C.,Scott, F.L.,Drag, M.,Swartz, P.,Mattos, C.,Salvesen, G.S.,Clark, A.C.
A constitutively active and uninhibitable caspase-3 zymogen efficiently induces apoptosis.
Biochem.J., 424:335-345, 2009

PubMed Abstract: The caspase-3 zymogen has essentially zero activity until it is cleaved by initiator caspases during apoptosis. However, a mutation of V266E in the dimer interface activates the protease in the absence of chain cleavage. We show that low concentrations of the pseudo-activated procaspase-3 kill mammalian cells rapidly and, importantly, this protein is not cleaved nor is it inhibited efficiently by the endogenous regulator XIAP (X-linked inhibitor of apoptosis). The 1.63 A (1 A = 0.1 nm) structure of the variant demonstrates that the mutation is accommodated at the dimer interface to generate an enzyme with substantially the same activity and specificity as wild-type caspase-3. Structural modelling predicts that the interface mutation prevents the intersubunit linker from binding in the dimer interface, allowing the active sites to form in the procaspase in the absence of cleavage. The direct activation of procaspase-3 through a conformational switch rather than by chain cleavage may lead to novel therapeutic strategies for inducing cell death.

PubMed: 19788411
DOI: 10.1042/BJ20090825

Experimental method

X-RAY DIFFRACTION (1.63 Å)